Neurofibrillary inclusions composed of the microtubule associated protein tau (tau) are a hallmark feature ot the pathology in several neurodegenerative diseases including Alzheimer's disease, Progressive supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). A causal link between tau dysfunction and neurodegeneration was demonstrated by the idenification of mutations in tau that give rise to FTDP-17. The overall goal of this current program is to identify modifiers that influence the progression of tau pathology, in human neurodegenerative disease and to build on this information to identify therapeutic targets that will form the basis for eventual patient treatments. This goal follows on naturally from the progress made in the first period of funding in which this Program was highly successful in developing both cell culture and transgenic animal models of tauopathy as well as in characterizing the genetic causes of these diseases. The four projects, alongwith a central Neuropathology core, that make up this program will address this overall goal through different but complementary strategies. Project 1 (Dr Farrer) will utilize a genetic approach to identify tau gene variants that increase the risk for developing 4R tauopathy (PSP and CBD) and will determine the mechanism by which these variants lead to disease. This project will thus define a potential therapeutic target in these diseases. Project 2 (Dr Yen) will utilize a cell culture model of early stage tau filament formation and pathogenesis to study the impact of several factors that have been suggested as causes of tauopathy (eg oxidative stress, proteasome inhibition). This project will identify modifiers of tau pathogenesis in this cell model that can then be studied in our transgenic models. Projects 3 (Hutton) and 4 (Duff) will employ transgenic mouse models of tauopathy developed by the Program over the past 4 years to study potential targets already identified by preliminary studies. Project 3 will study the impact of the chaperone Hsp70 and its co-chaperone CHIP on tau pathogenesis whilst Project 4, will examine the impact of tau phosphorylation on pathology and neurodegeneration.